Synthetic route to scopolamine and/or atropine

ABSTRACT

A synthetic route to scopolamine and/or atropine. In such context, the present invention identifies a method for preparing 6,7-dehydro atropine, which can be converted into either scopolamine and/or atropine, along with a method for converting a protected pyrrole into a tetrachlorobicylic compound, such as benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. ApplicationNo. 17/450,254, filed Oct. 7, 2021, the teachings of which areincorporated by reference.

FIELD

The present invention is directed to a synthetic route to scopolamineand/or atropine. In such context, the present invention identifies amethod for preparing 6,7-dehydro atropine, which can be converted toeither scopolamine and/or atropine. Also disclosed is a method forconverting a protected pyrrole into a tetrachlorobicylic compound, suchas benzyl 3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.

BACKGROUND

In the 1970′s, the department of defense (DOD) developed the Mark 1nerve agent antidote kit which contained atropine and 2-PAM 2:

Atropine protects against the surge of acetylcholine by blocking theacetylcholine receptor sites in the synapse (called antagonism) while2-PAM 2 reactivates the inhibited AChE. Atropine primarily interactswith the muscarinic receptors (a receptor sub-type), which protects theheart and the lungs from the effects of organophosphourous nerve agents(OPNAs). Unfortunately, it does not interact with the nicotinicreceptors (another receptor sub-type) which are located primarily in thebrain and central nervous system (CNS), leaving the brain criticallyunprotected during OPNA exposure. Recent studies on (-)-scopolamine,however, have shown that it interacts with the nicotinic receptors,making it an attractive candidate for protection against OPNA CNSsymptoms.

Currently scopolamine is isolated from plants in the Solanaceae family,such as belladonna (Atropa belladonna) and the corkwood tree (Duboisialeichhardtii). See, S.F. Hagels, H. Hagels and O. Kayser, Phytochem Rev2017, 16, 333-353.

These plants must be farmed, dried, pulverized and the compoundsextracted and purified by chromatography to yield only 2-4% (w/w)scopolamine which generates significant waste. Two corporations,Boehringer Ingelheim and Alkaloids corporation have reported onprocesses that accomplish this approach, but the high demand coupledwith the relatively slow growth rates of the plant have made itrelatively difficult to procure the quantities needed to evaluate thiscompound as an OPNA antidote. Additional problems in the supply havebeen encountered due to yearly crop yield fluctuations as a result ofadverse weather events, pests, or disease. Moreover, the global demandfor scopolamine (3) is estimated to be about 2450 kg, which isanticipated to grow. Isolation for natural sources, however, will likelybecome more relatively expensive on larger scales

There are other relevant prior art reaction sequences that have beenreported in the literature. See, Hayakawa, Y.; Baba, Y.; Makino, S.; andNoyori, R., J Am Chem Soc. 1978, 100 1786-1791. Here, Noyori utilized areductive dipolar cycloaddition between a carbomethoxypyrrole andtetrabromoacetone to form, after dehalogenation, the tropenone.Reduction of the tropenone with diisobutyl aluminum hydride (DIBAL-H)then furnished 6-tropen-3α-ol or8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol.

In addition, reference is made to the work of Dobo et al, which reportedon a synthesis of scopolamine, starting from tropane-3α,6β-diol, whichwas converted into 3α-acetoxy-6-ene and then into O-acetylscopine(3α-acetoxy-6β, 7β-epoxytropane). Hydrolysis, followed by acylation withO-acetyltropoyl chloride and hydrolysis gave scopolamine. See, Dobo, P.;Fodor, G.; Janzso, G.; Koczor, J.; Toth, J.; and Vincze, I., J. Chem.Soc. 1959, 3461-3465. Some weaknesses of this approach are considered tobe the use of acetates to protect parts of the molecules from reaction,and the use of Fe₂(CO)₉ and tetrabromoacetone, both of which arerelatively expensive and relatively toxic.

Accordingly, it is an objective of the present invention to develop analternative approach for the synthesis of scopolamine and/or atropine,along with underlying intermediate reactions that facilitate such goal.

SUMMARY

A method for preparing 6,7-dehydro atropine comprising:

-   (a) providing a protected pyrrole having the following formula:

-   

-   wherein R may be an alkyl group, phenyl group, or benzyl group;

-   (b) reacting the protected pyrrole with pentachloroacetone and    forming a first tetrachloro-bicyclic compound having the following    formula:

-   

-   wherein R may be an alkyl group, phenyl group, or benzyl group

-   (c) carrying out a reductive dechlorination of the first    tetrachloro-bicyclic compound and forming a second bicyclic compound    having the following formula:

-   

-   wherein R may be an alkyl group, phenyl group, or benzyl group;

-   (d) carrying out a reductive methylation of the second bicyclic    compound formed in step (c) and forming or    8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following    formula:

-   

-   (e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into    6,7-dehydro tropine tosylate having the following formula:

-   

-   wherein ⁻OTs is reference to ⁻OSO₂-Ar-CH₃; and

-   (f) converting 6,7-dehydro tropine tosylate into 6,7-dehydro    atropine having the following formula:

-   

A method of converting a protected pyrrole into a tetrachlorobicyliccompound comprising:

-   a. providing a protected pyrrole having the following formula:

-   

-   wherein R may be an alkyl group, phenyl group, or benzyl group;

-   b. reacting the protected pyrrole with pentachloroacetone and    forming a tetrachloro-bicyclic compound having the following    formula:

-   

-   wherein R may be an alkyl group, phenyl group, or benzyl group.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 . illustrates the oxidation of compound 7, 6,7-dehydro atropine,followed by a reductive work-up.

DETAILED DESCRIPTION

The present invention is directed to a synthetic route to scopolamineand/or atropine. In the initial step, a protected pyrrole is provided.One can therefore utilize an alkyl, phenyl or benzyl carbamate protectedpyrrole which can be achieved by treatment of pyrrole with a substitutedchloroformate Cl-CO-OR, where R can be an alkyl group (e.g. methyl,ethyl propyl), a phenyl group, a substituted phenyl group, or a benzylgroup:

Preferably, the pyrrole herein is protected by treatment with sodiumhydride followed by quenching upon addition of benzyl chloroformate(ClCOOBn) at -78° C., in a preferred tertiary butanol (tBuOH) andtetrahydrofuran (THF) solvent media, to yield a benzyl carbamateprotected pyrrole at yields of around 95%:

In the next step shown below, the preferred benzyl carbamate protectedpyrrole 2 is reacted with pentachloroacetone (PCA or Cl₃COC(Cl)₂H) inthe preferred solvent hexfluroisopropanol (HFIPA) in the presence of thepreferred organic base N-methylmorpholine (NMM), which organic base ispreferably at a concentration of 0.5 M, providing the compound 3, benzyl2,2,4,4-tetrachloro-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate, in86% yield:

With regards to the use of pentachloracetone (PCA) for the conversion ofcompound 2 to compound 3, it was recognized herein that the PCA can bepreferably prepared from hexachloroacetone (HCA), in situ, in thepresence of a trialkyl- or triaryl- phosphite having the formula POR₃where R can be an alkyl group (e.g., methyl, ethyl, propyl) or a phenylmoiety. A particularly preferred phosphite is triphenyphosphite(P(OPh)₃). In addition, one may utilize a trialkyl- or triaryl phosphinehaving the formula PR₃ where R can again be alkyl groups (e.g., methyl,ethyl propyl) or a phenyl moiety.

Reductive dechlorination of benzyl2,2,4,4-tetrachloro-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylateprovides compound 4, benzyl3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate, in greater than 90 %yield. More specifically, compound 3 is exposed to a reducing agent,preferably Zn, a tertiary amine (NR₃ wherein R is an alkyl group such asa methyl, ethyl and/or propyl group), more preferably tetramethylenediamine (TMEDA), an organic acid such as acetic acid (AcOH), in anorganic alcohol such as methanol (MeOH) according to the followingreaction scheme:

Reductive methylation of compound 4 and formation of a tosylate saltfollows. Preferably, compound 4 is reacted in tetrahydrofuran solvent(THF) in the presence of dibutyl aluminum hydroxide (DIBAL-H) to reducethe ketone moiety followed by addition of lithium aluminum hydride(LiALH₄) to reduce the carbamate, at preferred reaction temperatures of-78° C. to room temperature (r.t.), resulting in compound 5(6-tropen-3a-ol or 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol), at yieldsof at or over 80%:

Compound 5 is then treated with p-toluene sulfonic acid (pTSA) in apreferred acetone solvent which provides compound 6, 6,7-dehydro tropinetosylate, at yields of at or over 65%. In the formula below, ⁻OTs isreference to ⁻OSO₂-Ar-CH₃:

Compound 6 is then converted to compound 7, 6,7-dehydro atropine, atyields of at or above 80.0 %. Specifically, coupling of tropic acid tocompound 6 was preferably achieved by use of tropic acid having anorgano-silicon protective group. One therefore preferably employs atertbutyldimethylsilyl (TBS) protected tropic acid which then can reducethe risk of side reactions that may occur during its removal. Thiscoupling reaction preferably proceeds in the presence ofmethylnitrobenzoic acid anhydride (MNBA), triethyl amine (TEA), in anorganic solvent, such as methylene chloride. Then, deprotection of theorgano-silicon protective group proceeds via the use of methanol (MeOH)buffered with acetic acid (AcOH) in the presence of ammonium fluoride(NH₄F).

Compound 7, 6,7-dehydro atropine, can then be converted into compound 8,scopolamine and/or compound 9, atropine. The conversion to scopolaminepreferably proceeds via oxidation of compound 7 in an organic solvent.Preferably, oxidation in the presence of manganese sulfate (MnSO₄) andhydrogen peroxide (H₂O₂) in an organic solvent (DMF) in the presence ofsodium bicarbonate followed by a reductive work-up with sodium hydrogensulfite (NaHSO₃) in methanol (MeOH), which provides a 25% yield ofscopolamine (46% based on recovered starting material). The reductivework-up with NaHSO₃ reduced the amine oxides of compound 7, 8, 9 back tothe corresponding amines. The general scheme is set out below. The morespecific scheme is illustrated in FIG. 1 .

In addition, it is contemplated that the MnSO₄ in the above reactionscheme may be utilized, preferably at a 1:1 molar ratio, with a ligand,from the family of porphyrin, diamine and picolinic acid compoundsillustrated below, where R may be an alkyl group (e.g., methyl, ethyl,propyl) or an aryl group:

As alluded to above, compound 7, 6,7-dehydro atropine may also undergoreduction into compound 9, atropine. Preferably, one can employs adiimide reduction, where the diimide is provide from hydrazine (H2N2),in the presence of copper sulfate (CuSO₄) in ethanol (EtOH) media, whichprovides atropine at yields of 50%. The role of the CuSO₄ catalyst is tooxidize hydrazine to diimide in situ:

As may now be appreciated, the present invention identifies a newsynthetic pathway, that allows for the ability to isolate scopolamineand/or atropine (OPNA antidotes) at the indicated yields, and in alimited number of steps, from pyrrole. Such synthetic pathway offerswhat is contemplated to be a significant improvement over currentprocedures for isolating such antidotes, an example of which is nowcircumventing the reliance on Duboisia leichhardtii as the source ofscopolamine, while more efficiently meeting expanding global demands ofnerve agent remedies.

What is claimed is: 1-15. (canceled)
 16. A method for preparing6,7-dehydro atropine comprising: (a) providing a protected pyrrolehaving the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group; (b)reacting the protected pyrrole with pentachloroacetone and forming afirst tetrachloro-bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group; (c)carrying out a reductive dechlorination of said firsttetrachloro-bicyclic compound and forming a second bicyclic compoundhaving the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group; (d)carrying out a reductive methylation of the second bicyclic compoundformed in step (c) and forming or8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol having the following formula:

(e) converting 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol into6,7-dehydro tropine tosylate having the following formula:

wherein ⁻OTs is reference to ⁻OSO₂-Ar-CH₃.
 17. The method of claim 16,wherein R is a benzyl group, said first tetrachloro-bicyclic compoundcomprises benzyl2,2,4,4-tetrachloro-3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate andsaid second bicyclic compound comprises benzyl3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.
 18. The method ofclaim 16, wherein in step (b), said reaction of said pyrrole withpentachloroacetone takes place in the presence of N-methylmorpholine.19. The method of claim 16, wherein in step (b), pentachloroacetone isprovided in situ from hexachloroacetone.
 20. A method of converting aconverting a protected pyrrole into a tetrachlorobicylic compoundcomprising: a. providing a protected pyrrole having the followingformula:

wherein R may be an alkyl group, phenyl group, or benzyl group; b.reacting the protected pyrrole with pentachloroacetone and forming atetrachloro-bicyclic compound having the following formula:

wherein R may be an alkyl group, phenyl group, or benzyl group.
 21. Themethod of claim 20, wherein pentachloroacetone is provided in situ fromhexachloroacetone.
 22. The method of claim 20, wherein R is a benzylgroup and said tetrachlorobicyclic compound comprises benzyl3-oxo-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate.